The Neurocritic

Tuesday, July 31, 2007

In yesterday's story, EVERYTHING IS WRONG[...about protein synthesis and memory formation], The Neurocritic mentioned a potentially portentous new paper (Canal et al., 2007) that appears to question a [mostly] accepted theory that the formation of new memories requires de novo protein synthesis:

...the presumption is that protein synthesis inhibitors interfere with the establishment of enduring neural changes (i.e., those fundamental to memory, drug relapse, epilepsy, or motor cortex organization) by blocking mechanisms of neuronal and synaptic change that require de novo protein synthesis. Thus, evidence obtained with protein synthesis inhibitors has a pervasive influence on theories related to the fundamental mechanisms of not only memory formation but also a wide range of brain functions.

Although the protein synthesis view is predominant, the authors go on to cite data inconsistent with this notion (albeit data that's been basically ignored), and describe results so off the charts, it's surprising no one has noticed these effects before:

The findings described in the present article indicate that intraamygdala anisomycin injections result initially in extraordinarily large increases in release of biogenic amines near the site of injection, followed later by extensive and prolonged decreases in release of the amines. Additionally, blockade of amygdala beta-adrenergic receptors at the time of anisomycin injections, i.e., at the time of high release of biogenic amines, attenuates the amnesia produced by anisomycin as tested 48 h after training. Similarly, activation of beta2-adrenergic receptors during the time of amine depletion also attenuates anisomycin-induced amnesia assessed at 48 h after training. Moreover, a high dose of NE injected into the amygdala before training impairs memory to an extent similar to that seen after anisomycin injections. Together, these findings suggest that intraamygdala injections of anisomycin interfere with memory formation by inducing extraordinary changes in the release profiles of NE, DA, and 5-HT.

A critique of the microdialysis methods used in this study is beyond the scope of this blog, but any expert commentary is welcome.

Finally, appropriately timed administration of the beta-adrenergic antagonist propranolol and the beta-adrenergic agonist clenbuterol attenuated (but did not eliminate) the anisomycin-induced amnesia. Furthermore, a relatively high dose of norepinephrine injected into the amygdala 20 min before training produced amnesia for the inhibitory avoidance task when tested 48 hr later. No anisomycin necessary. At this stage, one can only speculate on the significance of these findings for the future of PTSD treatment.

Sunday, July 29, 2007

...about protein synthesis and memory formation, apparently. In keeping with the general theme of propranolol as a "memory eraser," a brand new iconoclastic paper (Canal, Chang, & Gold, 2007) claims that massive fluctuations in neurotransmitter levels (including norepinephrine, whose receptors are the target of beta blockers like propranolol; also dopamine and serotonin) -- rather than inhibition of protein synthesis (e.g., Doyere et al., 2007) -- are responsible for the amnestic quality of drugs like anisomycin:

Neuroscientist Paul E. Gold and colleagues have demonstrated that new protein synthesis is not required for long-term memory formation, a discovery that challenges basic assumptions about the mechanisms of memory....

. . .

Brain researchers have long used drugs that enhance or hinder memory formation to gain insight into the mechanisms at play. Early experiments in rats found that protein synthesis inhibitors injected into brain regions involved in memory processing could disrupt long-term memory formation. This led some to hypothesize that new protein synthesis was essential to the creation of long-term memories.

A research team led by neuroscientist Paul E. Gold discovered an alternate explanation for this effect. The researchers observed that the protein synthesis inhibitor anisomycin, which is commonly used in memory studies, causes dramatic changes in brain chemistry – apart from protein synthesis inhibition – that interfere with memory formation. They found that exposing rat brains to anisomycin sets off wild fluctuations in neurotransmitter levels in the brain region targeted in the experiment – the amygdala, one of several brain structures involved in processing memories and emotions. Large fluctuations in neurotransmitter levels in the amygdala are known to interfere with memory formation.

If this paper is correct, the results invalidate the premise of much previous research in the field [at the very least, regarding the mechanism of action for anisomycin in memory studies]. More later, hopefully...

Amnesia produced by protein synthesis inhibitors such as anisomycin provides major support for the prevalent view that the formation of long-lasting memories requires de novo protein synthesis. However, inhibition of protein synthesis might disrupt other neural functions to interfere with memory formation. Intraamygdala injections of anisomycin before inhibitory avoidance training impaired memory in rats tested 48 h later. Release of norepinephrine (NE), dopamine (DA), and serotonin, measured at the site of anisomycin infusions, increased quickly by ~1,000–17,000%, far above the levels seen under normal conditions. NE and DA release later decreased far below baseline for several hours before recovering at 48 h. Intraamygdala injections of a beta-adrenergic receptor antagonist or agonist, each timed to blunt effects of increases and decreases in NE release after anisomycin, attenuated anisomycin-induced amnesia. In addition, similar to the effects on memory seen with anisomycin, intraamygdala injections of a high dose of NE before training impaired memory tested at 48 h after training. These findings suggest that altered release of neurotransmitters may mediate amnesia produced by anisomycin and, further, raise important questions about the empirical bases for many molecular theories of memory formation.

When reactivated, memories enter a labile, protein synthesis–dependent state, a process referred to as reconsolidation. Here, we show in rats that fear memory retrieval produces a synaptic potentiation in the lateral amygdala that is selective to the reactivated memory, and that disruption of reconsolidation is correlated with a reduction of synaptic potentiation in the lateral amygdala. Thus, both retrieval and reconsolidation alter memories via synaptic plasticity at selectively targeted synapses.

Thursday, July 26, 2007

A new fMRI paper (Grosbras et al., 2007) examined the hemodynamic response[an indirect reflection of neural activity] in 10 yr old children who were watching videos of angry faces and gestures (versus neutral faces and gestures and control stimuli, see Fig 1 below). The authors wanted to see whether there were differences in the way that kids who are susceptible to peer pressure respond to these stimuli, relative to those who are resistant to peer pressure. The kids who are better able to resist peer pressure [at least, as measured by self-report on Steinberg and Monahan's resistance to peer influence questionnaire] showed more "coordinated" neural activity across a network of brain regions related to decision making and the perception of action than did the more easily influenced kids.

Fig 1 (Grosbras & Paus, 2006). Stimuli. Snapshots were taken at the beginning of representative clips of each condition. The video clips were displayed at 30 frames/s. Two consecutive images on the figure are separated by five frames.

Across all 35 participants [the data from 11 were thrown out due to excessive head motion],

the observation of hand movements engaged frontoparietal and middle temporal regions. Angry hand movements also recruited part of the parietal operculum/supramarginal gyrus, the medial prefrontal cortex, and the amygdala. The observation of angry or neutral faces engaged the premotor cortex, various parts of the inferior and medial frontal cortex, the fusiform cortex, the superior temporal sulcus, and the amygdala.

Next, an inverse correlation between RPI score and increased activity while watching angry hand or face movements (relative to neutral) was noted in the right dorsal premotor cortex and the left mid-dorsolateral prefrontal cortex. This means the less able to resist peer pressure, the greater the activity in those frontal areas. Hmm.

More sensitive children might engage more attentional resources when presented with salient stimuli such as angry hand movements.

both (1) regions involved in action observation, from the frontoparietal as well as from the temporo-occipital system..., and (2) regions in the prefrontal cortex.

What does this mean? Didn't we see greater frontal activity in the "just say yes" children?

It is important to note the difference between the findings obtained with univariate and multivariate analyses here. Univariate, voxel-by-voxel correlation between the fMRI signal and RPI scores showed a more robust response in low-resistance children independently in the premotor cortex and the prefrontal cortex. The multivariate analysis, in contrast, revealed stronger interregional correlations, or functional connectivity, between these and other regions in high-resistance children. We speculate that these two phenomena reflect, respectively, higher sensitivity of low-resistance children to socially relevant input and higher interregional integration of such inputs in high-resistance children. It is possible that the brains of the children with high RPI engage automatically executive processes when challenged with relatively complex and socially relevant stimuli. Interestingly, the children with higher RPI were also those who performed better in (explicit) executive tasks.

SO the kids who are better able to resist peer-pressure showed better executive controlfunctions (no surprise there) and a higher correlation between prefrontal and posterior brain activity in response to those angry hands.

During the shift from a parent-dependent child to a fully autonomous adult, peers take on a significant role in shaping the adolescent's behavior. Peer-derived influences are not always positive, however. Here, we explore neural correlates of interindividual differences in the probability of resisting peer influence in early adolescence. Using functional magnetic resonance imaging, we found striking differences between 10-year-old children with high and low resistance to peer influence in their brain activity during observation of angry hand movements and angry facial expressions: compared with subjects with low resistance to peer influence, individuals with high resistance showed a highly coordinated brain activity in neural systems underlying perception of action and decision making. These findings suggest that the probability of resisting peer influence depends on neural interactions during observation of emotion-laden actions.

Hasbro first announced a repair program in February, after learning of 29 incidents in which children's fingers or hands became trapped in the ovens. Five of those incidents included burns. The recall involved toys with the model number 65805.

The CPSC said in its release Thursday the company has since received 249 reports of children's hands or fingers catching in the oven...

Body image was significantly more negative after viewing thin media images than after viewing images of either average size models, plus size models, or inanimate objects. ... Results support the sociocultural perspective that mass media promulgate a slender ideal that elicits body dissatisfaction. Implications for prevention and research on social comparison processes are considered.

A recent neuroimaging study (Friederich et al., 2007) evaluated the brain activity of non-eating disordered1 women as they viewed photographs of slim models and stylish interior designs. The stimuli were

Images of slim female bodies and interior design were provided by a women’s magazine. The images were selected from a larger database in a pilot study, if they were rated by 38 healthy female volunteers as (1) easy to recognize, (2) interesting and (3) provoking anxiety in self-comparison. ... The body shape images of fashion models depicted either the whole or part of the body (head excluded) of slim women dressed in clothes that revealed their shape (e.g., bikinis or body fitting sports clothing). The comparison (control) images were of interior designs (inanimate objects only, e.g., rooms containing designer cupboards, drawers, curtains, lights).

One weakness in the experimental design is that images of "average-sized" female bodies (or plus size models) were not included. This would seem to be an obvious comparison, as it would control for the appearance of bodies yet provoke lower anxiety ratings (in fact, one could run a pilot study to match the interior designs and everyday bodies on anxiety ratings).

A procedural aspect that was well-controlled was the task for each condition: compare one's own body/house to the ones in the pictures. Seems that comparing one's tiny apartment to Architectural Digest displays might induce greater anxiety in some individuals not included in the current study (the "Martha Stewart effect").

Some of these brain regions are associated with responses to fear and anxiety (e.g., amygdala, portions of the basal ganglia). In addition, scores on the Eating Disorder Examination Questionnaire (global score, shape concern, and weight concern measures) correlated with anxiety ratings. The authors noted that dissatisfaction with one's body is not limited to eating disordered (ED) populations, and suggested that ED prevention programs could incorporate training in the top-down control of emotional responses [perhaps indexed by PFC and ACC activity here] when comparing one's self to an overly thin model.

Footnote

1 For inclusion in the study, the participants had to have a body mass index between 17.5 and 25.0 kg/m2. The former value is right at the cutoff for anorexia. However, the mean BMI was a healthy 21.9, and the 16 participants had never received diagnoses of an eating disorder or other psychiatric illnesses.

References

Friederich HC, Uher R, Brooks S, Giampietro V, Brammer M, Williams SC, Herzog W, Treasure J, Campbell IC. (2007). I'm not as slim as that girl: Neural bases of body shape self-comparison to media images. Neuroimage Jun 2; [Epub ahead of print].The aim of the present study was to assess the impact of images of slim female fashion models on healthy young women. Brain responses to images of slim-idealized bodies (active condition) and interior designs (control condition) were measured using functional neuroimaging in 18 healthy young women. Instructions encouraged the participants to compare their own body shape/own home with the one in the images. Participants rated the level of anxiety that they experienced while exposed to the images. In the active relative to the control condition, participants activated body shape processing networks, including the lateral fusiform gyrus on both sides, the right inferior parietal lobule, the right lateral prefrontal cortex and the left anterior cingulate. The level of reported anxiety during the exposure to slim bodies correlated with established measures of shape and weight concern and with brain activations in bilateral basal ganglia, left amygdala, bilateral dorsal anterior cingulate, and left inferior lateral prefrontal cortex. Brain networks associated with anxiety induced by self-comparison to slim images may be involved in the genesis of body dissatisfaction and hence with vulnerability to eating disorders.

Monday, July 16, 2007

Fig. 1. (A) Experimental procedure [adapted from Depue et al., 2007]. Individuals were first trained to associate 40 cue faces with 40 nasty target pictures. During the fMRI phase, individuals viewed only faces. On some trials they were instructed to think of the previously learned picture; on other trials they were instructed not to let the previously associated picture enter consciousness [no-think]. The presentation of only the cue (i.e., the face) ensures that individuals manipulate the memory of the target picture. Additional faces not shown during this phase acted as a behavioral baseline. During the test phase, participants were shown the 40 faces and asked to describe the previously associated picture.

Can you selectively and willfully forget (or at least, suppress) the past, particularly the most negative events? Not with a drug or ECT, but by using your brain's intrinsic "executive control"1 abilities? As mentioned the other day in I Forget, the promise of propranolol has been overhyped. But can PTSD patients (and others with traumatic memories) be trained to forget their waking nightmares? Can one harness the intrinsic plasticity of the brain to "unlearn" (rather than learn)? As Dr. Michael Merzenich wrote recently:

BRAIN PLASTICITY IS A TWO-WAY STREET. It is “negative” plasticity that generates the changes in the brain that underly the impaired operational state of the depressed or stressed or anxious or obsessed or traumatized individual. PTSD, for example, is a PRODUCT of brain plasticity. Just as I can plausibly create a positive brain plasticity-based approach to re-normalize the brain of the PTSD patient, so, too, can I create the malady itself, at will, by training the brain in ways that drive specific “negative” changes within it.

These questions were not answered by a brand new fMRI paper in Science (Depue et al., 2007), but a more modest goal was to determine whether the neural activity (or rather, the hemodynamic response) in certain brain regions dipped below baseline levels when participants were actively trying to suppress thinking about unpleasant pictures (see above) that were paired with neutral faces. The study adapted the "think/no-think" paradigm of Dr. Michael C. Anderson (et al., 2001, 2004), who heads the Memory Control Lab at the University of Oregon.

Similar to Anderson and Green, in the Think condition, participants were told "Think of the picture previously associated with the face", whereas in the No-Think condition they were told "Do not to let the previously associated picture come into consciousness." Within each condition (Think/No-Think), participants viewed the faces 12 times. The 8 faces not shown in the experimental phase served as a zero-repetition behavioral baseline.

The behavioral manipulation was effective in suppressing memory: mean recall rates were 71.1% in the think condition, compared to 53.3% in the no-think condition. Baseline recall was 62.5% (when subjects viewed the face-picture pair only in the training phase, but did not get 12 presentations of the face only in the experimental phase).

What were the brain imaging results? First, let's look at the data from the 2004 experiment of Anderson et al., which used word pairs as stimuli (e.g., roach-ordeal, steam-train, jaw-gum) instead of face-picture pairs.

Fig. 2 (Anderson et al., 2004). Activation for Suppression trials compared with Respond trials during the think/no-think phase. Areas in yellow were more active during Suppression trials than during Respond trials, whereas areas in blue were less active during Suppression (P less than 0.001, uncorrected). White arrows highlight hippocampal deactivation in the Suppression condition.

Furthermore, the degree of activity in bilateral DLPFC and left VLPFC [and a few other places] was related to an individual's ability to suppress remembering in the no-think condition (Anderson et al., 2004). So were the results similar in the current study, or did they differ due to the use of yucky pictures (from the IAPS) as the suppressed stimuli?

Prefrontal regions, right-sided and spanning BA 8, 9/46, 47, and BA 10, exhibited NT > T contrast. A conjunction analysis indicated that these differences resulted from an increase in activity for NT trials rather than a decrease in activation for T trials relative to baseline (Fig. 2A), which suggests that these regions are specifically involved in controlling the suppression of emotional memories.

Brain areas underlying the sensory representation of memory that showed such an effect [NT greater than T, NT negative relative to baseline, and T positive relative to baseline] were the visual cortex, including bilateral BA17, BA18, and BA37 [fusiform gyrus (FG)], and the pulvinar nucleus of the thalamus (Pul; Fig. 2B). Suppression of emotional memories thus involved decreased activity in sensory cortices that are normally active when memories are being retrieved, as well as in regions (i.e., Pul) that play a role in gating and modulating attention toward or away from visual stimuli.

And the hippocampus and amygdala showed no-think reductions in activity (Fig 2C), as would be expected for structures involved in memory and emotion, respectively.

Finally, the authors divided the data up into quartiles based on the order of experiment trials -- i.e., Q1 was comprised of trials 1-3, Q2 was 4-6, etc. to reveal the two phases of memory suppression:

Two patterns of temporal change in activation were observed, each associated with different groupings of prefrontal and posterior brain areas. The two groupings were composed of (i) right inferior frontal gyrus (rIFG), Pul, and FG, and (ii) right middle frontal gyrus (rMFG), Hip, and Amy[Hip and Amy! love the abbreviations!] ... rIFG showed early activation in the time course of suppression, which lasted through the second quartile of repetitions... Greater activity in rIFG in the second quartile was significantly associated with decreased activity in Pul and FG during the second quartile...

In contrast to rIFG, rMFG activation increased later and remained active. Activity in Hip and Amy appeared to follow that of rMFG in reverse... Increased activity in rMFG did not predict activity in Hip and Amy in the first or second quartiles, but did so significantly in the third and fourth quartiles.

But who's controlling these controllers? Why, Brodmann area 10 (frontopolar cortex) is the orchestra's conductor! And that's not all! It seems to me that the hippocampus showed a wacky pattern of activity.

New research suggests that people can push out memories, even highly emotional ones, simply by deciding to do so.

The researchers believe the new findings will help scientists understand disorders like post-traumatic stress disorder and obsessive-compulsive disorder, in which the brain's mechanism of suppressing unwanted memories may be dysfunctional, said lead author Brendan Depue, a graduate student in neuroscience and clinical psychology at the University of Colorado at Boulder.

But many experts are wary of linking the findings -- published today in the online journal Science -- to debilitating disorders like PTSD. They believe the mind developed to actively forget some memories to keep from cluttering the brain with unpleasant memories and irrelevant information, like unnecessary phone numbers. But highly emotional memories may never be forgotten.

"We have these mechanisms to try to stamp out and suppress these things when we want to try to avoid uncomfortable thoughts. On the other hand, we do know that very serious emotional memories are, in general, very remembered," UC Berkeley psychologist Art Shimamura said.

. . .

Dr. Thomas Neylan, a PTSD expert at the San Francisco Veterans Affairs Medical Center, said training in memory suppression is not the goal of treatment in many disorders. "Effective treatment (in PTSD) is to promote a new form of learning," he said. "When a person retrieves the memory of the trauma, they no longer associate it with all the same feelings of fear and arousal. With repetition, they are no longer as aroused, upset or angry. That process involves a new form of learning, not memory suppression."

Forgetting the most traumatic parts of one's past would seem to be of benefit to the lead singer of Linkin Park (as it would be to many of us). And now you can!! [according to recent reports in the press.] The first irresponsible story is old hat at this point (i.e, more than a week old), but since news cycles last for, oh, about 24 seconds these days [before collective amnesia supposedly sets in], let's review some of the most egregious headlines:

Do you have a really bad memory, or past heartache, that you would prefer to forget?

Researchers at Harvard and McGill University (in Montreal) are working on an amnesia drug that blocks or deletes bad memories. The technique seems to allow psychiatrists to disrupt the biochemical pathways that allow a memory to be recalled.

In a new study, published in the Journal of Psychiatric Research, the drug propranolol is used along with therapy to "dampen" [not delete, after all?] memories of trauma victims....

It failed to bring Jim Carrey happiness in the award-winning film Eternal Sunshine of the Spotless Mind, but scientists have now developed a way to block and even delete unwanted memories from people's brains.

Researchers have found they can use drugs to wipe away single, specific memories while leaving other memories intact. By injecting an amnesia drug at the right time, when a subject was recalling a particular thought, neuro-scientists discovered they could disrupt the way the memory is stored and even make it disappear.

So what about propranolol for PTSD? According to Strawn & Geracioti (2007),

The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.

So you might imagine that the discerning and jaded eye would be skeptical if confronted with the latest headline:

You can forget the unhappy past: studyBy Ishani GanguliWASHINGTON (Reuters) - Researchers have confirmed what common wisdom has long held -- that people can suppress emotionally troubling memories -- and said on Thursday they have sketched out how the brain accomplishes this.They said their findings might lead to a way to help patients with post-traumatic stress disorder or anxiety to gain control of debilitating memories."You're shutting down parts of the brain that are responsible for supporting memories," said Brendan Depue, a neuroscience doctoral student at the University of Colorado who worked on the study. He said his team discovered the brain's emotional center is also shut down.

Whether memories can be suppressed has been a controversial issue in psychology and cognitive neuroscience for decades. We found evidence that emotional memories are suppressed via two time-differentiated neural mechanisms: (i) an initial suppression by the right inferior frontal gyrus over regions supporting sensory components of the memory representation (visual cortex, thalamus), followed by (ii) right medial frontal gyrus control over regions supporting multimodal and emotional components of the memory representation (hippocampus, amygdala), both of which are influenced by fronto-polar regions. These results indicate that memory suppression does occur and, at least in nonpsychiatric populations, is under the control of prefrontal regions.

The β-adrenergic blocker propranolol given within hours of a psychologically traumatic event reduces physiologic responses during subsequent mental imagery of the event. Here we tested the effect of propranolol given after the retrieval of memories of past traumatic events. Subjects with chronic post-traumatic stress disorder described their traumatic event during a script preparation session and then received a one-day dose of propranolol (n = 9) or placebo (n = 10), randomized and double-blind. A week later, they engaged in script-driven mental imagery of their traumatic event while heart rate, skin conductance, and left corrugator electromyogram were measured. Physiologic responses were significantly smaller in the subjects who had received post-reactivation propranolol a week earlier. Propranolol given after reactivation of the memory of a past traumatic event reduces physiologic responding during subsequent mental imagery of the event in a similar manner to propranolol given shortly after the occurrence of a traumatic event.

The catecholamine norepinephrine is a critical effector of the mammalian stress response and has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD) -- a syndrome intrinsically related to the experience of extraordinary stress. Symptom-linked hypernoradrenergic derangements have been observed in PTSD and several studies have examined the potential therapeutic effects of agents that dampen the centrally hyperactive noradrenergic state. These agents include compounds that decrease norepinephrine release (e.g. centrally acting alpha(2) agonists such as clonidine) and those which block post-synaptic norepinephrine receptors (e.g. centrally acting alpha(1) or beta receptor antagonists such as prazosin or propranolol). In this article, we review studies of central noreadrenergic hyperactivity under both basal and challenge conditions and explore the evidence for these derangements as potential psychopharmacologic targets in patients with PTSD. Given the significant involvement of CNS norepinephrine hyperactivity in PTSD, and its link to intrusive and hyperarousal symptoms, it is not surprising that interventions directed at this system have therapeutic potential in PTSD. The utility of these anti-adrenergics in the clinical treatment of PTSD remains to be determined, though it is possible that they may prove to have primary roles in a disorder that is only modestly responsive to antidepressant treatment.

Wednesday, July 11, 2007

Washington, D.C. − In what they call a "stunning research advance," investigators at Georgetown University Medical Center have been able to use simple, non-toxic chemical injections to add and remove fat in targeted areas on the bodies of laboratory animals. They say the discovery, published online in Nature Medicine on July 1, could revolutionize human cosmetic and reconstructive plastic surgery and treatment of diseases associated with human obesity.

"Make me beautiful"

In the paper, the Georgetown researchers describe a mechanism they found by which stress activates weight gain in mice, and they say this pathway -- which they were able to manipulate − may explain why people who are chronically stressed gain more weight than they should based on the calories they consume.

This pathway involves two players -- a neurotransmitter (neuropeptide Y, or NPY) and the receptor (neuropeptide Y2 receptor, or Y2R) it activates in two types of cells in the fat tissue: endothelial cells lining blood vessels and fat cells themselves. In order to add fat selectively to the mice they tested, researchers injected NPY into a specific area. The researchers found that both NPY and Y2R are activated during stress, leading to apple-shape obesity and metabolic syndrome. Both the weight gain and metabolic syndrome, however, were prevented by administration of Y2R blocker into the abdominal fat.

"We couldn’t believe such fat remodeling was possible, but the numerous different experiments conducted over four years demonstrated that it is, at least in mice; recent pilot data also suggest that a similar mechanism exist in monkeys as well," said the study's senior author, Zofia Zukowska, M.D., Ph.D., professor and chair of the Department of Physiology & Biophysics at Georgetown University Medical Center.

"We are hopeful that these findings might eventually lead to control of metabolic syndrome, which is a huge health issue for many Americans," she said. "Decreasing fat in the abdomen of the mice we studied reduced the fat in their liver and skeletal muscles, and also helped to control insulin resistance, glucose intolerance, blood pressure and inflammation. Blocking Y2R might work the same way in humans, but much study will be needed to prove that."

"Perfect mind"

Fig. 1 (Warne & Dallman, 2007) - A new role for neuropeptide Y.Kuo et al. focus on the direct effects of neuropeptide (NPY) on adipocyte physiology in repeatedly stressed animals fed a palatable high-fat diet. NPY acts on preadipocytes, endothelial cells and macrophages to promote adipocyte proliferation and maturation as well as to induce new capillaries to supply nutrients to the increased fat mass. NPY is secreted from sympathetic nerve terminals in response to stressors. The blockade of either NPY receptors or glucocorticoid receptors blocks the abdominal obesity that occurs with stressors and a high-fat diet. [Katie Ris]

And perhaps the most rapid clinical application of these results will be in both cosmetic [see Nip/Tuck] and reconstructive plastic surgery, said co-author Stephen Baker, M.D., D.D.S, associate professor of plastic surgery at Georgetown University Hospital. The ability to add fat as a graft would be useful for facial rejuvenation, breast surgery, buttock and lip enhancement, and facial reconstruction, he said, and using injections like those tested in this study could make fat grafts predictable, inexpensive, biocompatible and permanent.

Equally important, blocking Y2R resulted in local elimination of adipose, or fat, tissue, said Baker. "This is the first well-described mechanism found that can effectively eliminate fat without using surgery,” he said. “A safe, effective, non-surgical means to eliminate undesirable body fat would be of great benefit to our patients."

The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.

Friday, July 06, 2007

The Neurocritic would also like to thank Dr. Walterfang for drawing our attention to a terrible new disease afflicting quantitative neuroimaging laboratories around the globe. The sweatshop conditions contributing to this pandemic must end!

The explosion in psychiatric neuroimaging research has led to the establishment of stressful and dark neuroimaging laboratories in which young researchers sweat in front of computer monitors performing laborious and tedious imaging analysis. These conditions have contributed to the development of a new psychiatric syndrome, described below.

Read the Diagnostic criteria to see if you, too, might be affected. As a cautionary tale, read the Case report of a 38-year-old psychiatrist who spent hundreds of hours tracing hippocampal volumes on MRI scans.

Figure 2 (Velakoulis et al., 2007): Anterior cingulate region showing inter-state differences in cortical thickness, overlaid on a geographic map of Australia. The region-of-interest corresponded to the portion of the anterior cingulate gyrus anterior to the black line, and was delineated on the reconstructed cortical surface, as shown.

The Neurocritic covered the dueling Australian cinguli back in May. The experiment revealed that Melbourne residents have a substantially thicker anterior cingulate cortex (ACC) than Sydney residents, and this difference remained highly significant when controlling for age and intracranial volume. One of the study's authors, Dr. Mark Walterfang, commented on that post, and has made the uncorrected proof available in a blog exclusive.

The hypotheses were as follows:

-- Australian Football League (AFL) premierships won by each city would be associated with greater cortical thickness due to the endorphin-mediated release of neurotrophins, and a relative lack of cortisol-related neuronal loss.

-- Median 2005 property prices would be associated with reduced cortical thickness due to the atrophic effects of high levels of circulating cortisol in stressed mortgagees.

-- Cortical thickness would be greatest in the city with the higher intellectual capital as measured by the number of 2005 NHMRC grants.

The results indicated that Sydney residents did come up with the short end of the stick for all measures:

...the other variables compared to ACC thickness measures suggested that Sydney-siders were subject to higher property prices, a lower number of successful NHMRC grant applications, and significantly less success with respect to the number of AFL premierships won.

Clearly, this is a landmark study that inaugurates the nascent field of Sociocompetitive Neuroscience (aka the Neurobiology of Civic Rivalry).

Thursday, July 05, 2007

Toddlers learn their first words better from people than from Teletubbies.

But the initial comparison (discussed in the press release) wasn't between live Teletubbies and live people, or between televised Teletubbies and televised people, but between televised Teletubbies and live people.

Children younger than 22 months may be entertained, but they do not learn words from the television program, said Marina Krcmar, associate professor of communication at Wake Forest and author of the study.

"With the tremendous success of programs such as 'Teletubbies' that target very young children, it has become important to understand what very young children are taking away from these programs," Krcmar said. "We would like to think it could work, that Teletubbies and other programs can teach initial language skills. That is not true."

In the study, Krcmar evaluated the ability of children ages 15 -- 24 months to learn new words when the words were presented as part of a "Teletubbies" program. She then evaluated their ability to learn the new words from an adult speaker in the same room with them.

However, it was good to see mention of the appropriate comparison at the end of the press release:

As part of the study, Krcmar also found that the children were just as attentive to an adult speaker on the small screen as they were to the Teletubbies characters. And, the children identified the target words more successfully in response to a video of an adult speaker than to the Teletubbies.

The results appeared in the journal Media Psychology. I don't have online access to the article, but one question is whether the researchers considered Teletubby Talk:

It appears not. And what do the show's creators say about language acquisition?

The show's co-creator Andy Davenport studied speech sciences before embarking on a career in children's TV. So the development of Teletubby talk came about through a combination of his experience and observing children closely.

"We thought long and hard about the way the Teletubbies should speak," says Andy. "After a lot of thought we came up with a play language based on the early speech of a young child. To small children, Teletubby words carry as much meaning as normal words."

This study was inspired by the rise in television targeting toddlers and preverbal infants (e.g., Teletubbies, Baby Mozart). Overall, we investigated if very young children who are in the early stages of language acquisition can learn vocabulary quickly (fast map) from television programs. Using a fast mapping paradigm, this study examined a group (n = 48) of toddlers (15—24 months) and their ability to learn novel words. Utilizing a repeated measures design, we compared children's ability to learn various novel words in 5 different conditions. These included the presentation and identification of a novel word by an adult speaker via live presentation when the toddler was attending (i.e., joint reference), an adult via live presentation when the toddler was not attending, an adult speaker on television, and an edited clip from a children's television program (Teletubbies). Overall, the toddlers were most successful in learning novel words in the joint reference condition. They were significantly less successful in the children's program condition. Furthermore, there was a significant interaction between age and condition on children's performance. Both younger (15—21 months) and older (22—24 months) participants identified the target objects when they were taught the novel word by an adult speaker; however, it appeared that children under the age of 22 months did not identify the target item when they were taught the novel word via the television program.

He [Simon Plant, landlord] said that the Ashas were model tenants, but that Dr. Asha, a Palestinian with Jordanian citizenship, had something of a condescending manner. "He got a slight attitude," said Mr. Plant, an elevator engineer. "He had a sense of self-importance about being a doctor. You could definitely feel it."

. . .

Dr. Asha, 26, whose specialty is neurosurgery, recently started work at the North Staffordshire Hospital in Stoke-on-Trent. According to the General Medical Council in Britain, Mohammed Jamil Abdelqader Asha completed his medical studies in Jordan in 2004. His limited registration allowed him to work for the National Health Service under supervision. Until last July, he worked as a doctor at Royal Shrewsbury Hospital and the Princess Royal Hospital, both in Telford.

Sunday, July 01, 2007

from Bentin et al. (2007):Supplementary Figure 4.B. These histograms derived from Thierry et al.'s (2007) data provides the best illustration that ISPV cannot account for N170 amplitude, showing an inverse relationship between within-category picture similarity (highest for faces) and N170 amplitude (highest for cars) in the low ISPV condition and similar N170 amplitudes for faces and cars in the high ISPV condition despite lower picture similarity for faces than cars (Experiment 1).

The Phineas Gage Fan Club has noted the publication of a letter to the editor in Nature Neurosciencethat's critical of the ISPV paper published by Thierry et al. (2007a) in April. What's ISPV? That's interstimulus perceptual variance, and it was a factor purportedly uncontrolled in prior studies of the N170, an electrophysiological signal thought to be selective for faces (see Are Faces Special?). The specificity of the N170 for faces (vs. other objects) is part of a larger debate on whether faces have a privileged processing status or not (the latter view being that faces are just one example of a stimulus class that requires substantial expertise in order to distinguish between similar exemplars). Then the recent NN paper added more fuel to the fire.

Briefly, in their original article, Thierry et al. argued that previous studies of the N170 component did not adequately control for variability across stimulus classes, i.e., face stimuli were much more similar to each other than the non-face stimuli. When ISPV was more tightly controlled, the selectivity of N170 for faces (vs. cars) went away.

Here we [Bentin et al.] demonstrate that ISPV was actually controlled in many studies, yet the N170 effect remained conspicuous (Fig. 1 and Supplementary Figures 1,2,3 online). Evidently, Thierry and colleagues' claim is wrong and misleading.

Continuing merrily along:

In addition to their factual error, they failed to note the striking contradiction between their hypothesis and the existing literature. Most notable are the larger N170 for inverted than for upright faces, the larger N170 for upright than for inverted Mooney faces..., [etc.] All these modulations of N170 are robust despite identical stimuli in different conditions, hence identical ISPV.

My favorite, however, is the title for Supplementary Figure 4: "Self-contradictions in Thierry et al.":

Supplementary Figure 4.A. While Thierry et al. claimed to have controlled for inter-stimulus similarity between pictures of faces and objects (exact values not reported), their own data suggest otherwise.

About Me

Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.